U.S. patent number 6,727,401 [Application Number 09/022,504] was granted by the patent office on 2004-04-27 for pressure sensitive adhesive matrix patch for the treatment of onychomycosis.
This patent grant is currently assigned to Watson Pharmaceuticals, Inc.. Invention is credited to Danyi Quan, Srinivasan Venkateshwaran.
United States Patent |
6,727,401 |
Venkateshwaran , et
al. |
April 27, 2004 |
Pressure sensitive adhesive matrix patch for the treatment of
onychomycosis
Abstract
A device for treating antifungal infections of toenails and
fingernails is made up of an occlusive backing layer and a pressure
sensitive adhesive matrix layer in which is uniformly dispersed an
effective amount of an antifungal agent and, optionally, a chemical
enhancer. The matrix layer has a first surface adhering to the
backing layer and a second surface adapted to be in diffusional
contact with the infected nail and surrounding skin area. The
device is configured, when applied, to cover and adhere to the nail
and surrounding skin areas for an extended period of time without
causing irritation to the skin or inhibiting normal physical
activity while providing a continuous delivery of antifungal agent
to the infected area.
Inventors: |
Venkateshwaran; Srinivasan
(Salt Lake City, UT), Quan; Danyi (Salt Lake City, UT) |
Assignee: |
Watson Pharmaceuticals, Inc.
(Corona, CA)
|
Family
ID: |
21809930 |
Appl.
No.: |
09/022,504 |
Filed: |
February 12, 1998 |
Current U.S.
Class: |
602/41; 424/448;
424/449 |
Current CPC
Class: |
A61K
9/7061 (20130101); A61K 8/4946 (20130101); A61F
13/105 (20130101); A61Q 3/00 (20130101) |
Current International
Class: |
A61K
9/70 (20060101); A61Q 3/00 (20060101); A61K
8/30 (20060101); A61F 13/10 (20060101); A61K
8/49 (20060101); A61F 013/00 () |
Field of
Search: |
;602/41,22,30,31
;424/404,443,445-449 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
0 515 312 |
|
May 1992 |
|
EP |
|
WO 87/02580 |
|
May 1987 |
|
WO |
|
WO 95/23597 |
|
Sep 1995 |
|
WO |
|
Other References
J Faergemann, H Zehender, and L Millerioux, Levels of terbinafine
in plasma, stratum corneum, dermis-epidermis (without stratum
corneum), sebum, hair and nails during and after 250 mg terbinafine
orally once daily for 7 and 14 days. Clinical and Experimental
Dermatology, 19:121-126, 1994. .
H P Baden, The Physical Properties of Nail. The Journal of
Investigative Dermatology, 55(2): 115-122. .
M Johnson, J S Comaish, and S Shuster, Nail is Produced by the
Normal Nail Bed: A Controversy Resolved. British Journal of
Dermatology, 125: 27-29, 1991. .
D S Walters, and R K Scher, Nail Terminology. International Journal
of Dermatology, 34(9): 607-610, 1995..
|
Primary Examiner: Lo; Weilun
Assistant Examiner: Kidwell; Michele
Attorney, Agent or Firm: Thorpe, North & Western,
LLP
Claims
What is claimed is:
1. A device for the treatment of infections of the nail comprising:
(a) an occlusive backing layer and; (b) a matrix layer having a
first surface and a second surface opposite the first surface where
the first surface is adhered to the backing layer and the second
surface being adapted to be in diffusional contact with the nail
and surrounding skin, said matrix layer comprising: i) a pressure
sensitive adhesive; and ii) an amount of an antifungal agent which
is sufficient to provide an antifungal effect contained in said
adhesive, wherein said antifungal agent is a member selected from
the group consisting of: fluconazole, terbinafine, clotrimazole,
miconazole and ketoconazole, salts thereof, and a mixture thereof;
said device being configured such that, when applied to a nail, the
second surface of the matrix layer will be adhesively secured to
and cover the nail and surrounding skin area.
2. A device according to claim 1 wherein the antifungal agent is
present in amounts of between about 1% and 10% by weight of the
matrix layer.
3. A device according to claim 2 wherein the matrix layer
additionally uniformly contains an amount of a permeation enhancer
which is sufficient to increase permeation of the antifungal agent
into the nail and surrounding skin area.
4. A device according to claim 3 wherein the enhancer is present in
amounts of between about 0.1% to 30% by weight of the matrix
layer.
5. A device according to claim 4 wherein the pressure sensitive
adhesive is a member selected from the group consisting of acrylic,
urethane rubber, silicone adhesives, and a mixture thereof.
6. A method for the transdermal/transnail treatment of an infected
nail on a hand or foot with an antifungal agent comprising
adhesively securing to the nail and surrounding skin of said nail
an adhesive device comprising: (a) an occlusive backing layer; and
(b) a matrix layer, one surface of which is adhered to the backing
layer and the other surface being secured in diffusional contact
with the infected nail and the surrounding skin, said matrix layer
comprising: i) a pressure sensitive adhesive; and ii) an amount of
an antifungal agent which is sufficient to provide an antifungal
effect contained in said adhesive, wherein said antifungal agent is
a member selected from the group consisting of: fluconazole,
terbinafine, clotrimazole, miconazole, ketoconazole, salts thereof,
and a mixture thereof;
said device being adhesively secured to said nail and adjacent
surrounding skin area for a time sufficient to deliver an effective
amount of said antifungal agent to the area of infection.
7. A method according to claim 6 wherein the antifungal agent is
present in amounts of between about 1% and 10% by weight of the
matrix layer.
8. A method according to claim 7 wherein the matrix layer
additionally uniformly contains an amount of a permeation enhancer
which is sufficient to increase permeation of the antifungal agent
into the nail and surrounding skin area.
9. A method according to claim 8 wherein the enhancer is present in
amounts of between about 0.1% to 30% by weight of the matrix
layer.
10. A device according to claim 9 wherein the pressure sensitive
adhesive is a member selected from the group consisting of acrylic,
urethane rubber, silicone adhesives, and a mixture thereof.
Description
FIELD OF THE INVENTION
This invention relates to a device for the administration of a
pharmaceutical composition for treating fungal nail infections.
Particularly, the device has an occlusive backing which facilitates
the composition's migration into finger nails, toe nails and the
epidermis around the nails.
BACKGROUND OF THE INVENTION
Conditions such as onychomycosis pose serious problems in
dermatology. Onychomycosis is a condition recognized by
discoloration beneath toe nails and finger nails along with pain
when pressure is placed near or at the site of discoloration. The
condition usually affects more than one nail. Various fungi,
classified as white superficial fungi, cause the condition. The
prevalence of onychomycosis in the general population is in the
range of 2-13% and increases to about 15-20% in the 40-60 year old
age group.
The current treatment of onychomycosis generally falls into three
categories: systemic administration of antifungals; surgical
removal of all or part of the nail followed by topical treatment of
the exposed tissue; or topical application of conventional creams,
lotions, gels or solutions on the infected nail, frequently
including the use of bandages to keep these dosage forms in place
on the nails. All of these approaches have major drawbacks.
Long term systemic (oral) administration of an antifungal agent for
the treatment of onychomycosis has been required to produce a
therapeutic effect. For example, oral treatment with the antifungal
compound ketoconozole typically requires administration of 200 to
400 mg/day for 6 months before any significant therapeutic benefit
is realized. Such long term, high dose systemic therapy can have
significant adverse effects. For example, ketoconozole has been
reported to have liver toxicity effects and reduces testosterone
levels in blood due to adverse effects on the testes. Patient
compliance is a problem with such long term therapies especially
those which involve serious adverse effects.
Surgical removal of all or part of the nail followed by topical
treatment also has severe drawbacks. The pain and discomfort
associated with the surgery and the undesirable cosmetic appearance
of the nail or nail bed represent significant problems,
particularly for female patients or those more sensitive to
physical appearance.
Topical therapy has significant problems too. Topical dosage forms
such as creams, lotions, gels etc., do not keep the drug in
intimate contact with the nail for prolonged periods of time.
Bandages have been used to hold drug reservoirs in place in an
attempt to enhance absorption of the pharmaceutical agent. However
the bandages are thick, awkward, troublesome and generally lead to
poor patient compliance.
Hydrophilic and hydrophobic film forming topical antifungal
solutions have also been developed. These dosage forms provide
improved contact between the drug and the nail, but the films are
not occlusive. Moreover, topical formulations for onychomycosis
treatment have exclusively tried to deliver the drug to the target
site (an infected nail bed) by diffusion across or through the
nail.
Human nail is more like hair than stratum corneum with respect to
chemical composition and permeability. Nitrogen is the major
component of the nail attesting to the nail's proteinaceous nature.
The total lipid content of mature nail is 0.1-1.0%, while the
stratum corneum lipid is about 10% w/w. The nail is 100-200 times
thicker than the stratum corneum and has a very high affinity and
capacity for binding and retaining antifungal drugs. Consequently,
little if any drug penetrates through the nail to reach the target
site (the nail bed, see FIG. 4, number 16). Because of these
reasons, topical therapy for onychomycosis has generally been
ineffective.
Onychomycosis is a localized fungal infection of the nail plate and
nail bed. The ideal therapy for onychomycosis would maintain very
high local tissue concentration of an antifungal agent in the nail
and skin, and deliver effective amounts of drug topically to the
nail bed, with minimum systemic exposure. Matrix type skin patches
are well known in the art, but their advantages for the treatment
of onychomycosis have not been recognized. A matrix patch device
configured for application over the infected nail and surrounding
skin would overcome all the disadvantages of conventional topical
therapy for onychomycosis.
It would therefore be desirable to have a matrix patch device which
not only enabled the passage of drug compositions into the nail to
preclude additional invasive infection but which simultaneously
facilitated the transnail and transdermal administration of an
antifungal agent to treat the infection directly. The invention
herein described accomplishes this and other purposes.
SUMMARY OF THE INVENTION
Accordingly, it is a primary objective of the present invention to
provide a method for the transdermal/transnail delivery of
sufficient amounts of a suitable drug to an affected nail bed and
surrounding tissue.
It is an additional object of the present invention to provide a
method whereby an occlusive patch is adhered to the treatment site
such that the adhesive layer of the patch is maintained in direct
diffusional contact with the digit to be treated and where the
adhesive layer is adapted to deliver an antifungal agent to the
infected site.
These and other objects may be realized by means of an occlusive
device suitable for the transdermal and transnail delivery of
antifungal pharmaceutically-active agents which are lipophilic or
hydrophilic, including salts. The device comprises an occlusive
backing layer and a pressure sensitive matrix layer having a first
surface adhering to the backing layer and an opposite second
surface adapted to be in diffusional contact with the nail and
surrounding skin areas.
Matrix type skin patches are known in the art but none have
heretofore been developed and configured for application and
adhesion to the nail and surrounding skin areas. It has been
discovered that such an antifungal pressure sensitive adhesive
matrix patch renders it possible to saturate the nail plate with
very high concentration of an antifungal agent compared to systemic
dosing (with minimal systemic exposure) while administering the
antifungal drug to the nail bed, as the target site, via the nail
and skin around the nail at much higher rates than would be
possible through the nail alone. The invention provides penetrating
transdermal/transnail compositions based on the use of a
pharmaceutically-active agent dissolved in, or admixed with a
biocompatible pressure sensitive adhesive. It may also be
advantageous and even preferable to also include an effective
amount of one or more penetration enhancing agents as will be more
specifically identified below.
The drug enhancer combination is contained in an occlusive device
for purposes of holding the composition against the skin or nail
surface for administration. Such devices are patches configured for
adhesion to the nail surface including a portion of the surrounding
tissue in matrix form.
A matrix patch is one where in the drug/enhancer is admixed with a
pressure sensitive adhesive to form a matrix. Matrix patches are
formed by admixing the drug/adhesive and enhancer if present in a
fluid or spreadable form. A uniform depth or thickness of admixture
is spread or cast on a protective pealable release liner and a film
backing is placed on the opposite side of the admixture to form a
film sandwich with the drug/adhesive/enhancer in the center. The
film sandwich is then die cut into the appropriate size and pouched
in a protective pouch until ready for application. For use, the
pealable release liner is removed and the drug/adhesive/enhancer
matrix is applied directly to the nail and surrounding skin. The
drug and enhancer migrate from within the adhesive matrix to the
nail and skin surface. The enhancer, as here presented, functions
to increase the flux of drug through the skin and increase the
penetration of the drug into and through the nail. Importantly, the
occlusive backing of the patch holds the drug against the nail and
skin to increase the migration of the drug from the matrix patch
into the nail and associated skin.
BRIEF DESCRIPTION OF FIGURES
FIG. 1 is a top view of a digit with attached nail and one
embodiment of the matrix patch of the present invention.
FIG. 2 is a top view similar to FIG. 1 showing a second embodiment
of the patch.
FIG. 3 is a top view similar to FIG. 1 showing a third embodiment
of the patch.
FIG. 4 is a cross sectional view of a digit i.e. a toe,
illustrating the nail, nail bed and other anatomical portions of
the nail and surrounding skin area for optimal delivery of an
antifungal agents; where the matrix patch of the present invention
is also shown in cross section with the outer occlusive backing and
the matrix portion which contains and delivers the drug to the
tissue.
DETAILED DESCRIPTION OF FIGURES
FIG. 1 is a top view of a digit 12 with attached nail 11 and one
embodiment of the matrix patch, 10 of the present invention.
Importantly, it is preferred that the matrix patch cover a portion
of the nail, cuticle and epidermis in the nail region. Although the
embodiments shown in FIGS. 1, 2 and 3 depict three patch
embodiments showing variations as to patch size and geometry, all
three illustrate acceptable placement of the drug containing matrix
patch. The acceptable placement of the patch is shown to cover a
part or all of the infected nail, the cuticle and a portion of the
epidermis medial to the nail to be treated. It is important to
contact one if not all three of these portions with the drug
delivering matrix patch to promote the simultaneous
transdermal/transnail delivery of the medication.
FIG. 4 is a cross sectional view of a digit, 12 with nail 11,
epidermis 13, cuticle 14 and nail bed 16. This figure demonstrates
the anatomical relationship between the portion of the nail which
is typically in need of treatment, the nail bed 16, and the
surrounding physical barriers to its direct treatment, the nail 11,
epidermis 13 and cuticle 14. These formidable anatomic barriers
have, as discussed earlier, prevented meaningful treatment of
infections of the nail bed and associated tissues. This figure
presents an additional view of a preferred embodiment of the
present matrix patch 10 appropriately positioned so as to
adherently contact the epidermis 13, cuticle 14, and nail 11. As
depicted patch 10 consists of an impermeable backing 17 overlying a
matrix layer 18 in which the drug and enhancer, if present, are
uniformly distributed. As depicted in one preferred embodiment in
FIG. 1 where the matrix patch of the present invention extends to a
desired amount beyond the width of the digit being treated. This
additional length allows the matrix patch to be adhered to the
sides and perhaps the bottom (opposite the nail) of the treated
digit. This provides additional contact between the matrix patch of
the present invention and the epidermis tissue surrounding the nail
in need of treatment. In this manner the drug is administered to
the infected digit from numerous directions simultaneously. The
matrix patch of the present invention can thus deliver the
pharmaceuticle agent into the nail, through the cuticle and through
contacted epidermis simultaneously.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The following definitions, when used, will be helpful in describing
the invention and will eliminate the need for repetitive
explanations.
When used in context, the terms "enhancement," "penetration
enhancement" or "permeation enhancement" relate to an increase in
the permeability of a biological membrane (i.e. skin and/or nail)
to a drug, so as to increase the rate at which the drug permeates
through the membrane. The enhanced permeation effected though the
use of such enhancers can be observed, for example, by measuring
the rate of diffusion of the drug through animal or human skin
using a diffusion cell apparatus. The diffusion cell is described
by Merritt et al. Diffusion Apparatus for Skin Penetration, J. of
Controlled Release, 1 (1984) pp. 161-162.
By "afflicted situs" is meant a localized area of pathology,
discomfort, infection, inflammation or lesion, and the immediately
surrounding area, e.g. the nail and surrounding area of a finger or
toe.
By the term "permeant" or "drug" is meant any chemical material or
compound suitable for transdermal or transnail administration which
includes a desired biological or pharmacological effect by topical
application to the "affliction situs." In general, this includes
therapeutic agents such as antibiotics and antifungal agents. The
term "permeant" is also meant to include mixtures. By mixtures is
meant combinations of permeants from different categories, mixtures
of permeants from the same category and mixtures of free base and
salt forms of the same or different permeants from the same or
different categories.
By "effective" amount of a drug or permeant is meant a nontoxic but
sufficient amount of a compound to provide the desired local
effect. An "effective" amount of permeation enhancer as used herein
means an amount selected so as to provide the desired increase in
membrane permeability and, correspondingly, the desired depth of
penetration, rate of administration and amount of drug.
By "drug delivery system," "drug/enhancer composition" or any
similar terminology is meant a formulated composition containing
the drug to be transdermally or transnailly delivered in
combination with such pressure sensitive adhesives, penetration
enhancers, excipients, or any other additives.
By the term "matrix" or "matrix system" is meant an active permeant
homogeneously combined in a biocompatible pressure sensitive
adhesive which may or may not also contain other ingredients or in
which the enhancer is also homogeneously dissolved or suspended. A
matrix system is usually an adhesive patch having an impermeable
film backing and, before transdermal/transnail application, a
release liner on the surface of the adhesive opposite the film
backing. A matrix system therefore is a unit dosage form of a drug
composition in an adhesive carrier, also containing the enhancer
and other components which are formulated for maintaining the drug
composition in the adhesive in a drug transferring relationship
with the skin and nail.
As noted above, the drug delivery device is a matrix formulation
where the permeant and enhancer are incorporated into an adhesive
layer. In formulations where the enhancer is incorporated into the
adhesive, the enhancer will generally be present in amounts of
between about 0.1 to 30% by weight, preferably between about 1 to
20% by weight and most preferably between about 2 to 20% by weight.
The matrix device is brought in contact with the skin and nail at
the afflicted situs and is held in place by a suitable
adhesive.
It is to be understood that while the invention has been described
in conjunction with the preferred specific embodiments thereof,
that which follow are intended to illustrate and not limit the
scope of the invention. Other aspects of the invention will be
apparent to those skilled in the art to which the invention
pertains.
In the matrix systems the carrier is primarily the pressure
sensitive adhesive in which the enhancer and an effective amount of
an active permeant or drug are homogeneously combined.
Suitable pressure sensitive adhesives may include acrylic copolymer
adhesives or "acrylic adhesive," (e.g. National Starch Durotak
80-1196 and Monsanto Gelva 737), rubber based adhesives or "rubber
adhesive," such as polyisobutylene or "PIB adhesive," (e.g.
Adhesive Research MA-24) and silicone based adhesives or "silicone
adhesive," (e.g. Dow Bio-PSA). However, any other suitable pressure
sensitive adhesives may also be used which are compatible with the
active permeant and enhancer when utilized.
Suitable enhancers are well known in the art and may include
representative members selected from the group consisting of
a-hydroxy acids and fatty acid esters and amides thereof, fatty
alcohols, fatty acids, C.sub.1 to C.sub.8 esters of fatty acids,
C.sub.1 to C.sub.18 esters of glycerol and the like.
In matrix systems, the adhesive is present in amounts ranging from
50 to 99.75% by weight and will preferably be present in amounts of
between about 70 and 99.5% by weight. The enhancer is also
homogeneously dissolved or suspended in the adhesive matrix and
when present is present in amounts of between about 0.1-30% by
weight with ranges of between about 1 to 20% w being preferred and
2.0 to 15% w being most preferred.
EXAMPLES AND PREFERRED EMBODIMENTS
I. Skin Flux Methodology
In vitro human cadaver skin flux studies were conducted using
modified Franz non-jacketed permeation cells. The temperature of
the skin surface was maintained at 32.degree. C. by placing the
cells in a circulating water bath positioned over a stirring
module. The epidermal membrane was separated from the dermatomed
human cadaver skin by the heat-separation method of Kligman and
Christopher (Arch. Dermatol. 88:702 (1963)) involving the exposure
of the full thickness skin to 60.degree. C. heat for 60 seconds,
after which time the stratum corneum and the epidermis (epidermal
membrane) were gently peeled off the dermis.
For a matrix skin flux study, the heat separated human epidermal
membrane was cut into rectangular strips. The matrix was cut into
0.71 cm.sup.2 circular discs. The release liner was peeled and
discarded and the matrix disc was laminated onto the stratum
corneum surface of the epidermal membrane. The skin-matrix sandwich
was then loaded onto the diffusion cells. Each piece of the skin
matrix sandwich was loaded between the donor and receiver
compartments of a diffusion cell, with the epidermal side facing
the receiver compartment, and clamped in place. The receiver
compartment was then filled with 0.02% sodium azide aqueous
solution. The solubility of the drug in this medium is adequate to
ensure sink conditions throughout the experiment. The diffusion
cell was then placed in a circulating water bath calibrated to
maintain the skin surface temperature at 32.+-.1.degree. C. At
predetermined sampling intervals, the entire contents of the
receiver compartment were collected for drug quantitation and the
receiver compartment was filled with fresh receiver solution,
taking care to eliminate any air bubbles at the skin/solution
interface.
For the topical gel study, included for illustration purposes, a
thin film of gel approximately 10 .mu.l/cm.sup.2, was applied to
the stratum-corneum surface of a hydrated piece of human cadaver
skin. The skin was placed on top of the diffusion cell with the
epidermal side toward the receiver compartment and clamped in place
with an open-top lid. The gel was unoccluded and exposed to the
ambient conditions of the laboratory. At predetermined sampling
intervals, the entire contents of the receiver compartment were
collected for drug quantitation.
The cumulative amount of drug permeated per unit area at any time
t(Q.sub.t, .mu.g/cm.sup.2) was determined as follows: ##EQU1##
where C.sub.n is the concentration (.mu.g/ml) of the drug in the
receiver sample for the corresponding sample time, V is the volume
of fluid in the receiver chamber (.about.6.3 cm.sup.3), and A is
the diffusion area of the cell (0.64 cm.sup.2).
To determine the amount of drug retained in the skin, the patch was
removed from the skin after duration of study. Circular skin of
area 0.71 cm.sup.2 that was in contact with the matrix patch was
punched out. All punched skin pieces were dried overnight in an
oven at 36.degree. C., weighed and transferred to scintillation
vial containing 5 ml methanol as extraction solvent. The
scintillation vials were shaken in a gyrorotatory lab shaker for 12
hours and the amount of drug extracted in the solution was
analyzed.
II. Nail Flux Methodology
In vitro human cadaver nail flux studies were conducted using
modified Franz non-jacketed permeation cells. The temperature of
the nail surface was maintained at 32.degree. C. by placing the
cells in a circulating water bath positioned over a stirring
module. Human finger nail or toe nail was stored under frozen
conditions in 0.02% (w/v) sodium azide solution. Nails that were
greater than 1 cm.sup.2 in area were used for the flux studies.
Nails with dorsal side facing the donor compartment were sandwiched
between two layers of a closed cell polyethylene foam film. Annular
ring of 2.38 cm outer diameter and 0.95 cm inner diameter was cut
from the backing film. The area of the donut hole (0.97 cm.sup.2)
is large enough to provide complete contact with the receiver
media. The purpose of the foam backing film was to prevent any
leakage of receiver medium from the cell assembly. The nails were
allowed to hydrate at 32.degree. C. overnight with 0.02% (w/v)
sodium azide solution in the receiver compartment. The following
morning, 0.71 cm.sup.2 circular matrix patches were laminated onto
the dorsal side of the nail. Each nail matrix sandwich was then
loaded between the donor and receiver compartments of a diffusion
cell, with the ventral side of nail facing the receiver
compartment, and clamped in place.
To determine the amount of drug retained in the nails, the patch
was removed from the nail after duration of study. Circular nail of
area 0.71 cm.sup.2 that was in contact with the matrix patch was
punched out and examined. All punched nails were dried overnight in
an oven at 36.degree. C., weighed and transferred to scintillation
vial containing 5 ml dimethyl sulfoxide as extracting solvent. The
scintillation vials were shaken in a gyrotory lab shaker for 12
hours and the amount of drug extracted in the solution was
analyzed. The remaining portion of nail was also dried, weighed,
extracted in dimethyl sulfoxide and analyzed for drug content.
Completeness of extraction was verified by drying the extracted
nails, and re-extracting them in 3 ml dimethyl sulfoxide for 12
hours. No drug was seen when the re-extracted samples were
analyzed.
III. Nail Flux Studies
Example 1
Fluconazole is an antifungal drug, commonly used for systemic
fungal infections. Clinical studies have already proved that
fluconazole could be administered orally for treatment of
Onychomycosis. Matrix patches containing varying amounts of
antifungal agent and enhancers were prepared and tested. The matrix
systems consisted of 2 to 10% by weight of fluconazole, and 0 to
20% by weight of lauroyl lactylic acid as an enhancer in a medical
grade acrylic copolymer adhesive (Durotak 87-2516).
The matrix formulations were prepared as follows. First, the solids
content of the adhesive was determined by weighing a small amount
of the adhesive solution in a pre-weighed aluminum dish. The
solvent was evaporated by overnight drying in a convection oven
maintained at 70.degree. C. and the weight of the residue (dry
adhesive) and percent solid adhesive content of the solution was
determined. Once the solids content was determined, a known weight
of the acrylic copolymer adhesive solution was weighed into a glass
bottle. From the weight of the adhesive solution and the percent
solid adhesive content, the amount of adhesive in the solution was
calculated. The antifungal drug and the enhancers were added to the
bottle in the required proportions to yield the desired final
composition. The bottle was then tightly capped, sealed with
parafilm and rotated overnight until all ingredients had completely
dissolved and the resultant solution was visually clear.
Approximately 8 ml of the solution was then dispensed on a
silanized polyester release liner and cast with a 10 mil gap
casting knife. The casting was then dried in a convection oven at
70.degree. C. for 15 minutes to evaporate the solvent and to yield
a dried film approximately 2.0 mil thick. A 3 mil thick
polyethylene backing film was laminated onto the dried adhesive
film with a rubber roller. These matrix laminates were then used to
conduct in vitro nail flux studies as described. The results of the
nail flux experiments are presented in Tables 1 and 2.
TABLE 1 Formulation Composition Q.sub.t (t = 24) Q.sub.t (t = 48)
Q.sub.t (t = 72) Q.sub.t (t = 96) Q.sub.t (t = 144) A/D/E* (% w/w)
(.mu.g/cm.sup.2)** (.mu.g/cm.sup.2)** (.mu.g/cm.sup.2)**
(.mu.g/cm.sup.2)** (.mu.g/cm.sup.2)** A/D 94/6 0 0 0 0 9.04 .+-.
10.24 A/D/E 84/6/10 0 0 0 0 3.07 .+-. 3.88 *A = Adhesive, (Durotak
87-2516, an acrylic polymer); D = Drug, (Fluconazole); E =
Enhancer, (lauroyl Lactylic acid) **(Mean .+-. SD), n = 4 donors, 4
cell.
TABLE 2 Q.sub.t (t = 48) Q.sub.t (t = 48) Formulation Composition
(flux) (in the nail) A/D/E* (% w/w) (.mu.g/cm.sup.2)** (.mu.g/g)**
A/D/E 88/2/10 0 490.61 .+-. 146.71 A/D/E 86/4/10 0 1266.61 .+-.
408.78 A/D/E 84/6/10 0 1702.19 .+-. 882.61 A/D/E 82/8/10 0 2549.83
.+-. 969.55 *A = Adhesive, (Durotak 87-2516; an acrylic polymer) D
= Drug, (Fluconazole); E = Enhancer, (lauroyl lactylic acid).
**(Mean .+-. SD), n = 4 donors, 6 cell.
Table 1 shows that there is no permeation of fluconazole across the
nail up to 96 hours and very low amounts permeate after a week.
This illustrates that the nail is a formidable barrier to
penetration and only minute quantities of fluconazole can reach the
nail bed by permeation through the nail. Also, it can be seen from
Table 2 that significant amount of drug penetrates into and is
retained in the nail, illustrating the nail's capacity for binding
and retaining the drug. The amount of fluconazole retained in the
nail increases with increase in the drug concentration in the
formulation. However, it is noted that some permeation of the
antifungal agent through the nail was observed after 144 hours of
patch application according to the present invention.
Example II
The equilibration time of fluconazole into the nail was evaluated.
At each time point, the amount of drug (Q) in the nail per unit dry
weight of nail and the amount of drug in receiver media was
determined. There was no flux of fluconazole across the nails. The
amount of drug retained in the nails is shown in the tables
below.
TABLE 3 Composi- Formulation tion Q.sub.t (t = 24) Q.sub.t (t = 48)
Q.sub.t (t = 72) Q.sub.t (t = 96) A/D/E* (% w/w) (.mu.g/g)**
(.mu.g/g)** (.mu.g/g)** A/D 94/6 1985.96 .+-. 2513.49 .+-. 2178.54
.+-. 1570.46 .+-. 891.06 699.77 756.61 464.17 A/D/E 84/6/10 1894.06
.+-. 2137.26 .+-. 2095.13 .+-. 1571.91 .+-. 609.25 419.90 896.56
569.31 *A = Adhesive, (Durotak 87-2516, an acrylic polymer); D =
Drug, (Fluconazole); E = Enhancer, (lauroyl lactylic acid). **(Mean
.+-. SD), n = 4 donors, 4 cell.
TABLE 4 Formulation Composition Q.sub.t (t = 48) A/D/E* (% w/w)
(.mu.g/g)** A/D 94/6 1517.52 .+-. 569.92 A/D/E 89/6/5 2183.45 .+-.
303.36 *A = Adhesive, (Durotak 87-2516, acrylic polymer); D = Drug,
(Fluconazole); E = Enhancer, (sorbitan monooleate). **(Mean .+-.
SD), n = 4 donors, 7 cell.
It is seen from Tables 3 and 4 that the amount of fluconazole
partitioning into the nail reaches an equilibrium value within 24
hours. The literature reports that when 50 mg/day of fluconazole
was orally administrated for up to 14 days, the amount of
fluconazole in the nail was: 1.31 .mu.g/g at day 1 and 1.81 .mu.g/g
at day 14["Pharmacokinetic evaluation of fluconazole in skin and
nails," Hay R. J., International Journal of Dermatology, 1992 31
(supplement 2) page 6-7]. Clearly, the data in this example shows
approximately 1000-2000 times higher amounts of fluconazole in the
nail after 48 hours of patch application compared to the reported
amount of fluconazole in the nail after oral administration.
Example III
Terbinafine hydrochloride is another antifungal drug which is
approved for the treatment of Onychomycosis and other fungal
infections. Matrix systems were prepared as in Example 1. Flux of
terbinafine hydrochloride across the nail and the amount of drug in
the nail from matrix patch was also evaluated. The results are
given in Tables 5-6.
TABLE 5 Composi- Q.sub.t (t = 24) Q.sub.t (t = 48) Q.sub.t (t = 72)
Q.sub.t (t = 96) Formulation tion (.mu.g/ (.mu.g/ (.mu.g/ (.mu.g/
A/D/E* (% w/w) cm.sup.2)** cm.sup.2)** cm.sup.2)** cm.sup.2)** A/D
97.5/2.5 0 0 0 0 A/D/E 92.5/2.5/5 0 0 0 0 *A = Adhesive, (Durotak
87-2516, an acrylic polymer); D = Drug, (Terbinafine-HCl); E =
Enhancer, (triacetin). **(Mean .+-. SD), n = 2 donors, 2 cell.
TABLE 6 Composi- Q.sub.t (t = 24) Q.sub.t (t = 48) Q.sub.t (t = 72)
Q.sub.t (t = 96) Formulation tion (.mu.g/ (.mu.g/ (.mu.g/ (.mu.g/
A/D/E* (% w/w) cm.sup.2)** cm.sup.2)** cm.sup.2)** cm.sup.2)** A/D
97.5/2.5 57.19 .+-. 212.65 .+-. 72.68 .+-. 353.42 .+-. 22.33 267.17
17.26 29.24 A/D/E 92.5/2.5/5 76.53 .+-. 155.16 .+-. 212.81 .+-.
93.92 .+-. 28.04 156.36 233.03 11.92 *A = Adhesive, (Durotak
87-2516, an acrylic polymer); D = Drug, (Terbinafine-HCl); E =
Enhancer, (triacetin). **(Mean .+-. SD), n = 2 donors, 2 cell.
The results in Table 5 show that there is no permeation of
terbinafine across the nail up to 96 hours. However, significant
amount of drug penetrates into and is retained in the nail as shown
in Table 6. The amount of drug retained in the nail per unit dry
weight of nail was determined. The literature reports that when 250
mg/day of terbinafine was orally administrated for up to 14 days,
the amount of terbinafine in the nail was: 0.22 .mu.g/g at day 7
and 0.52 .mu.g/g at day 14["Levels of terbinafine in plasma,
stratum corneum, dermis-epidermis (without stratum corneum), sebum,
hair, and nails during and after 250 mg terbinafine orally once
daily for 7 and 14 days," Faergemann J, Zehender H, Millerious L.,
Clinical and Experimental Dermatology, 1994: 19, pgs 121-126].
Clearly, the results from Table 6 show Experimental Dermatology,
1994: 19, pgs 121-126]. Clearly, the results from Table 6 show
approximately 100-1000 times higher amount of terbinafine in the
nail after 48 hours of patch application compared to the amount of
terbinafine in the nail after the reported oral administration.
Example IV
Again following the procedure of Example 1. The flux of another
common antifungal drug, clotrimazole, across the nail and the
amount of drug in the nail from matrix patch was also evaluated.
The results are given in Tables 7-8.
TABLE 7 Composi- Q.sub.t (t = 24) Q.sub.t (t = 48) Q.sub.t (t = 72)
Q.sub.t (t = 96) Formulation tion (.mu.g/ (.mu.g/ (.mu.g/ (.mu.g/
A/D/E* (% w/w) cm.sup.2)** cm.sup.2)** cm.sup.2)** cm.sup.2)** A/D
94/6 0 0 0 0 A/D/E 84/6/10 0 0 0 0 *A = Adhesive, (Durotak 87-2516,
an acrylic polymer); D = Drug, (Clotrimazole); E = Enhancer,
(lauramide diethanolamine). **(Mean .+-. SD), n = 3 donors, 3
cell.
TABLE 8 Composi- Q.sub.t (t = 24) Q.sub.t (t = 48) Q.sub.t (t = 72)
Q.sub.t (t = 96) Formulation tion (.mu.g/ (.mu.g/ (.mu.g/ (.mu.g/
A/D/E* (% w/w) g)** g)** g)** g)** A/D 94/6 530.68 .+-. 777.36 .+-.
1052.34 .+-. 521.62 .+-. 536.30 196.19 885.93 244.22 A/D/E 84/6/10
213.38 .+-. 556.79 .+-. 601.80 .+-. 560.73 .+-. 73.12 320.24 503.26
273.84 *A = Adhesive, (Durotak 87-2516, an acrylic polymer); D =
Drug, (Clotrimazole); E = Enhancer, (lauramide diethanolamine).
**(Mean .+-. SD), n = 3 donors, 3 cell.
The results in Table 7 show that there is no permeation of
clotrimazole across the nail up to 96 hours. However, Table 8 shows
significant amount of drug penetrates into and is retained in the
nail. The amount of drug retained in the nail per unit dry weight
of nail after 48 hours of application of patch was greater than 500
.mu.g/g.
IV Skin Flux Studies
Example V
Following the procedure outlined above, the flux of fluconazole
across the human cadaver skin was evaluated in different studies.
The effect of increasing drug concentration on skin flux of
fluconazole and the amount of drug retained in the skin were also
determined. The results are presented in Tables 9-11 below.
TABLE 9 Formulation Composition Q.sub.t (t = 24) A/D/E* (% w/w)
(.mu.g/cm.sup.2)** A/D 94/6 47.43 .+-. 39.14 A/D/E 89/6/5 52.44
.+-. 55.51 *A = Adhesive, (Durotak 87-2516, an acrylic polymer); D
= Drug, (Fluconazole); E = Enhancer, (sorbitan monooleate). **(Mean
.+-. SD), n = 10 skins, 40 cells.
TABLE 10 Formulation Composition Q.sub.t (t = 24) A/D/E* (% w/w)
(.mu.g/cm.sup.2)** A/D/E 88/2/10 20.44 .+-. 12.39 A/D/E 86/4/10
41.17 .+-. 16.30 A/D/E 84/6/10 61.42 .+-. 31.21 A/D/E 82/8/10 53.68
.+-. 49.93 *A = Adhesive, (Durotak 87-2516, an acrylic polymer); D
= Drug, (Fluconazole); E = Enhancer, (lauroyl lactylic acid).
**(Mean .+-. SD), n = 3 skins, 12 cells.
TABLE 11 Q.sub.t (t = 24) Formulation Composition (in the skin)
A/D/E* (% w/w) (.mu.g/cm.sup.2)** A/D 94/6 6845.15 .+-. 1950.52
A/D/E 89/6/5 7473.76 .+-. 1590.36 *A = Adhesive, (Durotak 87-2516,
an acrylic polymer); D = Drug, (Fluconazole); E=Enhancer, (sorbitan
monooleate). **(Mean .+-. SD), n = 3 skins, 12 cells.
When compared with Example 1, the skin flux of fluconazole shown in
table 9 is much higher than the nail flux. It can be seen from
Table 10 that the optimal skin flux is observed with a formulation
containing 6% (w/w) fluconazole. Amount of fluconazole retained in
the skin after a flux of 24 hours is shown in Table 11. The
literature reported that when 50 mg/day of fluconazole was orally
administrated for up to 14 days, the amount of fluconazole in the
skin was: 11.70 .mu.g/g at day 1 and 24.15 .mu.g/g at day 14
["Pharmacokinetic evaluation of fluconazole in skin and nails," Hay
R. J., International Journal of Dermatology, 1992: 31 (supplement
2), pgs 6-7]. Clearly, the data in this example show approximately
500-600 times higher amount of fluconazole in the skin at 24 hours
compared to the amount of fluconazole in the skin at day 1 after
oral administration as reported in the literature. The effect of
different enhancers on the skin flux of fluconaaole, and the flux
with different adhesives were also evaluated. These results are
summarized in Tables 12-14.
TABLE 12 Formulation Composition Q.sub.t (t = 24) A/D/E* (% w/w)
(.mu.g/cm.sup.2)** A/D 94/6 54.88 .+-. 39.04 A/D/E 84/6/10 123.64
.+-. 61.99 *A = Adhesive, (Durotak 87-2516); D = Drug,
(Fluconazole); E = Enhancer, lauric diethanolamide. **(Mean .+-.
SD), n = 3 skins, 12 cells.
TABLE 13 Formulation Composition Q.sub.t (t = 24) A/D/E* (% w/w)
(.mu.g/cm.sup.2)** A/D 98/2 2.92 .+-. 2.67 A/D/E 88/2/10 4.39 .+-.
2.21 *A = Adhesive, (TSR, an acrylic polymer) D = Drug,
(Fluconazole); E = Enhancer, (lauroyl lactylic acid). **(Mean .+-.
SD), n = 3 skins, 12 cells.
TABLE 14 Formulation Composition Q.sub.t (t = 24) A/D/E* (% w/w)
(.mu.g/cm.sup.2)** A/D 90/10 27.42 .+-. 22.81 A/D/E 80/10/10 74.00
.+-. 21.93 *A = Adhesive, (Gelva-737, an acrylic polymer); D =
Drug, (Fluconazole); E = Enhancer, (lauroyl lactylic acid). **(Mean
.+-. SD), n = 2 skins, 8 cells.
The results shown in Table 12-14 illustrate the high skin flux of
fluconazole using various pressure sensitive adhesives with and
without the presence of an enhancer. Even without an enhancer,
there is sufficient flux shown to be somewhat effective. However,
the presence of an enhancer, such as lauroyl lactylic acid or
lauric diethanolamide significantly increases the flux in each
adhesive type. The high skin flux and skin retention is likely to
lead to lateral diffusion of drug into the nail bed.
Example VI
The effect of occlusion on the skin flux of fluconazole was
evaluated. Matrix systems of identical compositions with occlusive
or non-occlusive backing films were loaded on skin. The procedures
of Example 1 were followed with the exception that the casting was
with a 5 mil gap casting knife. The results are shown in Table 15
below.
TABLE 15 Formulation Composition Q.sub.t (t = 24) A/D/E* (%wlw)
Backing Film (.mu.g/cm.sup.2)** A/D 94/6 Occlusive 7.55 .+-. 5.97
A/D/E 84/6/10 Occlusive 32.66 .+-. 27.74 A/D 94/6 Non-occlusive
3.74 .+-. 1.16 A/D/E 84/6/10 Non-occlusive 6.87 .+-. 4.44 *A =
Adhesive, (Durotak 2516, an acrylic polymer); D = Drug,
(Fluconazole); E = Enhancer, (lauroyl lactylic acid). **(Mean .+-.
SD), n = 3 skins, 12 cells.
Without taking into consideration the mean deviations, in
formulations not containing an enhancer, the skin flux from the
formulation having the occlusive backing film shows about twice the
rate as with the formulation containing the non-occlusive backing.
In formulations containing an enhancer, the flux rate of the
occlusive formulation increases to about five times the rate on the
non-occlusive counterpart.
Example VII
Topical preparation of fluconazole were made on a 10 ml scale. Ten
milliliters of a solution made up of 65 parts by weight ethanol, 20
parts by weight water and 15 parts by weight glycerin was used as a
base. To this was added 600 mg of fluconazole in a vial which was
capped and ultrasonicated to completely dissolve the drug. Then 300
mg of hydroxypropylmethyl cellulose (Methocel E10M) was added as a
gelling agent and the contents were mixed thoroughly and gently
rotated overnight to completely dissolve the gelling agents. This
resulted in a gel having a gel/drug (G/D) weight composition of
about 94/6. The procedure mentioned above for the testing of
topical gels was followed, and the skin flux from the topical gel,
without occlusion, and a matrix patch having about the same drug
concentration, were compared. The results are given in Table
16.
TABLE 16 Formulation Composition Q.sub.t (t = 24) A/D* (% w/w)
(.mu.g/cm.sup.2)** A/D 94/6 11.41 .+-. 5.36 G/D 94/6 4.61 .+-. 2.34
*A = Adhesive, (Durotak 87-2516, an acrylic polymer); D = Drug,
(Fluconazole). **(Mean .+-. SD), n = 3 skins, 12 cells.
As shown in Table 16, the flux from the matrix systems is about 3
times higher than the flux from topical formulation.
Example VIII
Following the procedure from the above examples, the flux of
terbinafine hydrochloride across the human cadaver skin was
evaluated in different studies. The effect of increasing drug
concentration, and increasing enhancer concentration on skin flux
of terbinafine hydrochloride were evaluated. The amount of drug
retained on skin after application of the patch for 1 day was also
determined. The results are presented in Tables 17-19 below.
TABLE 17 Formulation Composition Q.sub.t (t = 24) A/D/E* (% w/w)
(.mu.g/cm.sup.2)** A/D 96/4 1.55 .+-. 0.40 A/D/E 87.5/4/8.5 2.73
.+-. 0.56 *A = Adhesive, (Durotak 87-2516, an acrylic polymer); D =
Drug, (Terbinafine-HCl); E = Enhancer, (Triacetin). **(Mean .+-.
SD), n = 3 skins, 12 cells.
The results shown in Table 17 illustrate the flux of
terbinafine-HCl using an acrylic pressure sensitive adhesive with
and without the presence of an enhancer. Even without an enhancer,
there is sufficient flux. However, the presence of an enhancer,
triacetin, significantly increases the flux.
TABLE 18 Formulation Composition Q.sub.t (t = 24) A/D/E* (% w/w)
(.mu.g/cm.sup.2)** A/D/E 91/1/8 0.77 .+-. 0.32 A/D/E 90/2/8 1.55
.+-. 0.52 A/D/E 89.5/2.5/8 2.32 .+-. 1.30 A/D/E 89/3/8 2.30 .+-.
1.26 *A = Adhesive, (Durotak 87-2516, an acrylic polymer); D =
Drug, (Terbinafine-HCl); E = Enhancer, (Triacetin). **(Mean .+-.
SD), n = 3 skins, 12 cells.
The results shown in Table 18 illustrate the flux of
terbinafine-HCl using an acrylic pressure sensitive adhesive with
and without the presence of an enhancer. Even without an enhancer,
there is sufficient flux shown to be somewhat effective. However,
the presence of an enhancer, triacetin, significantly increases the
flux.
TABLE 19 Formulation Composition Q.sub.t (t = 24) A/D/E* (% w/w)
(.mu.g/cm.sup.2)** A/D 97.5/2.5 0.77 .+-. 0.27 A/D/E 92.5/2.5/5
1.15 .+-. 0.40 A/D/E 87.5/2.5/10 1.73 .+-. 0.83 A/D/E 82.5/2.5/15
1.97 .+-. 0.41 A/D/E 77.5/2.5/20 3.05 .+-. 1.07 *A = Adhesive,
(Durotak 87-2516, an acrylic polymer); D = Drug, (Terbinafine-HCl);
E = Enhancer, (triacetin). **(Mean .+-. SD), n = 3 skins, 12
cells.
The results in Table 19 show that by increasing the triacetin
concentration there is a consistant increase in the skin flux.
Example IX
The flux of other representative antifungal agents, i.e.
clotrimazole, ketoconazole, and miconazole, in matrix formulations,
with and without enhancers, are evaluated in Tables 20-23.
TABLE 20 Formulation Composition Q.sub.t (t = 24) A/D/E* (% w/w)
(.mu.g/cm.sup.2)** A/D 95/5 0.00 .+-. 0.00*** A/D/E 85/5/10 18.40
.+-. 6.99 *A = Adhesive, (TSR, an acrylic copolymer); D = Drug,
(Clotrimazole); E = Enhancer, (glycolic acid). **(Mean .+-. SD), n
= 3 skins, 12 cells. ***Less than detection limit, which is Q.sub.t
.ltoreq. 3 .mu.g/cm.sup.2 /t.
These results indicate clotrimazole flux, without an enhancer, was
below the detection limit. However, in the presence of glycolic
acid as an enhancer there was significant flux from a matrix.
TABLE 21 Formulation Composition Q.sub.t (t = 24) A/D/E* (% w/w)
(.mu.g/cm.sup.2)** A/D 94/6 0.84 .+-. 0.28 A/D/E 84/6/10 2.45 .+-.
0.41 *A = Adhesive, (Durotak 87-2516, an acrylic polymer); D =
Drug, (Clotrimazole); E = Enhancer, (lauramide-diethanolamine).
**(Mean .+-. SD), n = 5 skins, 20 cells.
The results shown in Table 21 illustrate the flux of clotrimazole
using an acrylic pressure sensitive adhesive with and without the
presence of an enhancer. While there is measurable flux without an
enhancer, the presence of an enhancer, lauramide-DEA, significantly
increases the flux.
TABLE 22 Formulation Composition Q.sub.t (t = 24) A/D/E* (% w/w)
(.mu.g/cm.sup.2)** A/D 97/3 1.81 .+-. 0.62 A/D/E 87/3/10 3.41 .+-.
1.83 *A = Adhesive, (Durotak 87-2516, an acrylic polymer); D =
Drug, (Ketoconazole); E = Enhancer, (lauramide-diethanolamine).
**(Mean .+-. SD), n = 3 skins, 12 cells.
The results shown in Table 22 illustrate the flux of ketoconazole
using an acrylic pressure sensitive adhesive with and without the
presence of an enhancer. While there is some flux without an
enhancer, the presence of an enhancer, lauramide-DEA, doubles the
flux.
TABLE 23 Formulation Composition Q.sub.t (t = 24) A/D/E* (% w/w)
(.mu.g/cm.sup.2)** A/D 90/10 2.36 .+-. 1.12 A/D/E 70/10/20 4.38
.+-. 1.35 *A = Adhesive, (TSR, an acrylic polymer); D = Drug,
(Miconazole); E = Enhancer, (triacetin). **(Mean .+-. SD), n = 5
skins, 20 cells.
The results shown in Table 23 illustrate the flux of miconazole
using TSR as a pressure sensitive adhesive with and without the
presence of an enhancer. While there is some flux without an
enhancer, the presence of triacetin as an enhancer, significantly
increases the flux. These examples demonstrate how the matrix patch
of the present invention is able to simultaneously facilitate
significant drug flux across the epidermis and increase the
concentrations of the desired drug into the nail. This simultaneous
delivery provides a dual pathway attack for combatting the
infection. The administration of the antifungal agent into the nail
precludes additional migration or growth of the fungus further into
the nails and the administration of antifungal agents into the skin
around the nail facilitates a more direct application to the
infected area. In this manner, the matrix patch delivers the
antifungal agent into both the infected nail and the skin around
the nail, enhancing drug delivery to the infected area as compared
to previously known techniques, methods and compositions.
While certain antifungal agents, pressure sensitive adhesives and
enhancers have been primarily used for purposes of illustration,
other active agents, adhesives and enhancers may also be utilized
which result in transdermal/transnail flux and drug retention.
Example X
Matrix patch devices, as shown in FIG. 2, are prepared having
various surface areas sufficient to cover toe nails and surrounding
skin area of each toe on a foot. Each device consists of an
impermeable occlusive backing layer and a matrix layer of an
acrylic adhesive (Durotak 87-2516), fluconazole and a lauroyl
lactylic acid enhancer having the compositions shown in Table 2.
Patches are applied to the nails and surrounding skin of toes of
volunteers who wear patches for a period of up to four days without
restricting normal activity. Patches are shown to adhere to the
toes for the duration of the tests without causing skin irritation,
without affecting normal activity and without any noticable
discomfort. No attempt is made to determine skin flux or nail
retention of the drug.
Within the guidelines presented herein, a certain amount of
experimentation to obtain optimal formulations can be carried out
by those skilled in the art. What is important is that the matrix
system must be configured to cover the nail and surrounding skin
area of the digit being treated. The degree or distance of
surrounding skin coverage is limited only by the functionality of
the digit. In other words, there should be sufficient skin area
coverage to provide for flux of the drug through the skin layer to
the nail bed but not so much as to inhibit the flexability of the
digit. That can be readily determined by the size of the digit to
be treated. One or more digits of the same foot or hand may be
treated simultaneously. Therefore, the invention is limited in
scope only by the following claims and functional equivalents
thereof.
* * * * *